Combinations of acetaminophen with opioids (i.e., hydrocodone, codeine) are frequently prescribed for acute and chronic pain management. Combinations of analgesics with different mechanisms of action enhance analgesic efficacy while reducing the dose-dependent adverse effects of the individual components. Acetaminophen is a relatively safe, commonly used over-the-counter analgesic and antipyretic drug; however, ingestion of large doses can cause hepatotoxicity. Moreover, the analgesic tolerance, which evolves with repeated administration of opioid-containing combinations, is compensated by increasing the acetaminophen/opioid doses. This, in turn, increases the risk of acetaminophen-induced hepatic complications. Clearly physicians and patients will prefer analgesic combinations that have the fewest side effects and that provide a safer and more efficacious treatment for pain. The research in this SBIR project will optimize combinations of opioids and non-opioids with SCP-1. SCP-1 is the lead compound from St. Charles Pharmaceuticals's series of new proprietary derivatives of acetaminophen. SCP-1 has high analgesic activity but is free from antipyretic activity and hepatotoxicity. During phase I, we will use isobolographic analysis to demonstrate the feasibility of creating optimal doses within the combinations to obtain the synergistic effects with equal or higher efficacy and better safety profile than acetaminophen and opioid combination. We will determine the combinations that display the best onset and duration of analgesia and define their safety profiles by using GPT/GOT plasma activity and glutathione content in the liver and kidney. During Phase II, we will further characterize these SCP-1/opioid combinations looking for those combinations that are not antipyretics and are thus relevant to the treatment of post-surgical pain. Also the lead SCP-1 combinations will be evaluated for analgesia in other pain models such as chronic constriction injury and herpetic pain and we will undertake some of the preclinical studies using the selected combinations.